tbuckley/cabot-search huggingface dataset:
Early identification of axial psoriatic arthritis among patients with psoriasis: a prospective multicentre study
Authors: Fabian Proft, Susanne Lüders, Theresa Hunter, Gustavo Luna, Valeria Rios Rodriguez, Mikhail Protopopov, Katharina Meier, Georgios Kokolakis, Kamran Ghoreschi, Denis Poddubnyy
Journal: Annals of the Rheumatic Diseases (2022)

Objectives To evaluate a dermatologist-centred screening tool followed by a structured rheumatological examination including MRI of sacroiliac joints and spine for the recognition of psoriatic arthritis with axial involvement (axPsA). Methods This was a prospective multicentre study. Adult patients with a confirmed diagnosis of psoriasis who had chronic back pain (≥3 months), onset &lt;45 years and had not been treated with any biologic or targeted synthetic disease-modifying antirheumatic drug in the 12 weeks before screening were referred to a specialised rheumatology clinic. A rheumatological investigation including clinical, laboratory and genetic assessments as well as imaging with conventional radiography and MRI of sacroiliac joints and spine was performed. The primary outcome of the study was the proportion of patients diagnosed with axPsA among all referred patients with PsO. Results Rheumatologists examined 100 patients of those who qualified for referral. 14 patients (including 3 with both axial and peripheral involvement) were diagnosed with axPsA and 5 were diagnosed with peripheral PsA solely. All patients diagnosed with axPsA had active inflammatory and/or structural (post)inflammatory changes in the sacroiliac joints and/or spine on imaging. In five patients, MRI changes indicative of axial involvement were found only in the spine. All but one patient with PsA (13/14 with axPsA and 5/5 with pPsA) fulfilled the Classification Criteria for Psoriatic Arthritis criteria for PsA. The Assessment of SpondyloArthritis International Society criteria for axSpA were fulfilled in 9 (64.3%) patients diagnosed with axPsA. Conclusions Applying a dermatologist-centred screening tool may be useful for the early detection of axPsA in at-risk patients with psoriasis .
Infections in patients with rheumatoid arthritis receiving tofacitinib versus tumour necrosis factor inhibitors: results from the open-label, randomised controlled ORAL Surveillance trial
Authors: Andra-Rodica Balanescu, Gustavo Citera, Virginia Pascual-Ramos, Deepak L Bhatt, Carol A Connell, David Gold, All-Shine Chen, Gosford Sawyerr, Andrea B Shapiro, Janet E Pope, Hendrik Schulze-Koops
Journal: Annals of the Rheumatic Diseases (2022)

Objectives To characterise infections in patients with rheumatoid arthritis (RA) in ORAL Surveillance. Methods In this open-label, randomised controlled trial, patients with RA aged≥50 years with ≥1 additional cardiovascular risk factor received tofacitinib 5 or 10 mg two times per day or a tumour necrosis factor inhibitor (TNFi). Incidence rates (IRs; patients with first events/100 patient-years) and hazard ratios (HRs) were calculated for infections, overall and by age (50–&lt;65 years; ≥65 years). Probabilities of infections were obtained (Kaplan-Meier estimates). Cox modelling identified infection risk factors. Results IRs/HRs for all infections, serious infection events (SIEs) and non-serious infections (NSIs) were higher with tofacitinib (10&gt;5 mg two times per day) versus TNFi. For SIEs, HR (95% CI) for tofacitinib 5 and 10 mg two times per day versus TNFi, respectively, were 1.17 (0.92 to 1.50) and 1.48 (1.17 to 1.87). Increased IRs/HRs for all infections and SIEs with tofacitinib 10 mg two times per day versus TNFi were more pronounced in patients aged≥65 vs 50–&lt;65 years. SIE probability increased from month 18 and before month 6 with tofacitinib 5 and 10 mg two times per day versus TNFi, respectively. NSI probability increased before month 6 with both tofacitinib doses versus TNFi. Across treatments, the most predictive risk factors for SIEs were increasing age, baseline opioid use, history of chronic lung disease and time-dependent oral corticosteroid use, and, for NSIs, female sex, history of chronic lung disease/infections, past smoking and time-dependent Disease Activity Score in 28 joints, C-reactive protein. Conclusions Infections were higher with tofacitinib versus TNFi. Findings may inform future treatment decisions. Trial registration number NCT02092467 .
A Druggable Rheostat for Ewing Sarcoma?
Authors: Kurt R. Weiss, Kelly M. Bailey
Journal: Clinical Cancer Research (2022)

Summary The posterior HOXD enhancer is an EWSR1::FLI1-dependent regulator of HOXD13 expression in Ewing sarcoma. HOXD13 expression promotes a mesenchymal cell state. Through antagonistic transcriptional programs, EWSR1::FLI1 and HOXD13 serve as master regulators of Ewing cell plasticity. Targeting Ewing cells as they exist in/transition between mesenchymal states is a priority. See related article by Apfelbaum et al., p. 4466
Chronic glucocorticoid maintenance treatment is associated with the risk of SARS-CoV-2 infection in patients with systemic lupus erythematosus who received vaccination
Authors: Giuseppe A Ramirez, Lorenza Maria Argolini, Tommaso Schioppo, Savino Sciascia, Luca Moroni, Gabriella Moroni, Renato Alberto Sinico, Grazia Bonelli, Federico Alberici, Federica Mescia, Francesco Tamborini, Paolo Miraglia, Chiara Bellocchi, Lorenzo Beretta, Dario Roccatello, Enrica Paola Bozzolo, Roberto Caporali, Maria Gerosa, Lorenzo Dagna
Journal: Annals of the Rheumatic Diseases (2022)
Intracavity generation of glioma stem cell–specific CAR macrophages primes locoregional immunity for postoperative glioblastoma therapy
Authors: Chen Chen, Weiqiang Jing, Yu Chen, Ganyu Wang, Mohnad Abdalla, Lin Gao, Maosen Han, Chongdeng Shi, Anning Li, Peng Sun, Xin Jiang, Zhenmei Yang, Shengchang Zhang, Jing Zhang, Chunwei Tang, Ying Liu, Rui Zhang, Fengbo Xu, Baixiang Dong, Xueen Li, Minglu Liu, Bangming Qiang, Yanhua Sun, Xia Wei, Jun Li, Quanyin Hu, Xinyi Jiang
Journal: Science Translational Medicine (2022)

Glioblastoma multiforme (GBM) remains incurable despite aggressive implementation of multimodal treatments after surgical debulking. Almost all patients with GBM relapse within a narrow margin around the initial resected lesion due to postsurgery residual glioma stem cells (GSCs). Tracking and eradicating postsurgery residual GSCs is critical for preventing postoperative relapse of this devastating disease, yet effective strategies remain elusive. Here, we report a cavity-injectable nanoporter-hydrogel superstructure that creates GSC-specific chimeric antigen receptor (CAR) macrophages/microglia (MΦs) surrounding the cavity to prevent GBM relapse. Specifically, we demonstrate that the CAR gene–laden nanoporter in the hydrogel can introduce GSC-targeted CAR genes into MΦ nuclei after intracavity delivery to generate CAR-MΦs in mouse models of GBM. These CAR-MΦs were able to seek and engulf GSCs and clear residual GSCs by stimulating an adaptive antitumor immune response in the tumor microenvironment and prevented postoperative glioma relapse by inducing long-term antitumor immunity in mice. In an orthotopic patient–derived glioblastoma humanized mouse model, the combined treatment with nanoporter-hydrogel superstructure and CD47 antibody increased the frequency of positive immune responding cells and suppressed the negative immune regulating cells, conferring a robust tumoricidal immunity surrounding the postsurgical cavity and inhibiting postoperative glioblastoma relapse. Therefore, our work establishes a locoregional treatment strategy for priming cancer stem cell–specific tumoricidal immunity with broad application in patients suffering from recurrent malignancies.
Exocrine pancreas regeneration modifies original pancreas to alleviate diabetes in mouse models
Authors: Xiaoxing Kou, Jin Liu, Dandan Wang, Ming Yu, Can Li, Lu Lu, Chider Chen, Dawei Liu, Wenjing Yu, Tingting Yu, Yao Liu, Xueli Mao, Ali Naji, Tao Cai, Lingyun Sun, Songtao Shi
Journal: Science Translational Medicine (2022)

Diabetes is a major public health issue because of its widely epidemic nature and lack of cure. Here, we show that pancreas-derived mesenchymal stem cells (PMSCs) are capable of regenerating exocrine pancreas when implanted into the kidney capsule of mice with streptozotocin (STZ)–induced diabetes. Mechanistically, we found that the regenerated exocrine pancreas elevated interleukin-6 (IL-6) in PMSC implants, which transiently activated tumor necrosis factor–α (TNF-α) and interferon-γ (IFN-γ) to inhibit IL-17, thereby rescuing damaged exocrine pancreas and islet β cells. In addition, we used knockout mouse models to show that global lack of IL-6, TNF-α, or IFN-γ resulted in increased severity of STZ-induced diabetes and resistance to PMSC implantation therapy, confirming the roles of these factors in safeguarding pancreatic β cells. Furthermore, removal of the kidney capsule PMSC implants at 28 days after implantation did not affect the PMSC-initiated therapeutic effect on diabetic mice. This study reveals a previously unknown role of exocrine pancreas regeneration in safeguarding β cells and demonstrates a “soil-rescues-seed” strategy for type 1 diabetes therapy.
Publisher Correction: Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes
Authors: Catherine Schramm, Camille Charbonnier, Aline Zaréa, Morgane Lacour, David Wallon, Anne Boland, Jean-François Deleuze, Robert Olaso, Flora Alarcon, Dominique Campion, Grégory Nuel, Gaël Nicolas
Journal: Genome Medicine (2022)
Altiratinib blocks <i>Toxoplasma gondii</i> and <i>Plasmodium falciparum</i> development by selectively targeting a spliceosome kinase
Authors: Christopher Swale, Valeria Bellini, Matthew W. Bowler, Nardella Flore, Marie-Pierre Brenier-Pinchart, Dominique Cannella, Lucid Belmudes, Caroline Mas, Yohann Couté, Fabrice Laurent, Artur Scherf, Alexandre Bougdour, Mohamed-Ali Hakimi
Journal: Science Translational Medicine (2022)

The Apicomplexa comprise a large phylum of single-celled, obligate intracellular protozoa that include Toxoplasma gondii , Plasmodium , and Cryptosporidium spp., which infect humans and animals and cause severe parasitic diseases. Available therapeutics against these diseases are limited by suboptimal efficacy and frequent side effects, as well as the emergence and spread of resistance. We use a drug repurposing strategy and identify altiratinib, a compound originally developed to treat glioblastoma, as a promising drug candidate with broad spectrum activity against apicomplexans. Altiratinib is parasiticidal and blocks the development of intracellular zoites in the nanomolar range and with a high selectivity index when used against T. gondii . We have identified Tg PRP4K of T. gondii as the primary target of altiratinib using genetic target deconvolution, which highlighted key residues within the kinase catalytic site that conferred drug resistance when mutated. We have further elucidated the molecular basis of the inhibitory mechanism and species selectivity of altiratinib for Tg PRP4K and for its Plasmodium falciparum counterpart, Pf CLK3. Our data identified structural features critical for binding of the other Pf CLK3 inhibitor, TCMDC-135051. Consistent with the splicing control activity of this kinase family, we have shown that altiratinib can cause global disruption of splicing, primarily through intron retention in both T. gondii and P. falciparum . Thus, our data establish parasitic PRP4K/CLK3 as a potential pan-apicomplexan target whose repertoire of inhibitors can be expanded by the addition of altiratinib.
Letter to the editor: Successful treatment of multidrug‐resistant hepatis C after &gt;12 months of continuous therapy with direct‐acting antivirals
Authors: Wenhao Luo, Ying Zhang, Taiping Zhang
Journal: Hepatology (2022)

To the editor, We read the study by Trudeau et al., which presented a patient case with a history of multiple failed treatments who ultimately achieved sustained virological response (SVR) after an extended course of direct‐acting antiviral (DAA) regimens.1 However, we have some concerns about this conclusion. First, patients with hepatitis C virus (HCV) and cirrhosis may be subject to more medical and lifestyle monitoring after initial diagnosis and are vulnerable to many confounding factors. Recent study showed that common drug–drug interactions exist in glecaprevir–pibrentasvir (GLE‐PIB) or sofosbuvir–velpatasvir (SOF‐VEL) such as proton‐pump inhibitors, histamine‐2 receptor antagonists, and lipid‐lowering agents, which will affect the efficacy of GLE‐PIB or SOF‐VEL.2 In this study, no clear statement about the medical monitoring was shown. Moreover, interferon‐based combination regimes for patients with liver cirrhosis may have a higher risk of treatment‐associated serious adverse events.3 This study just regarded SVR as an important treatment outcome of the patient with HCV. However, the safety evaluation and complication after extended DAA therapies were not mentioned in the study. Secondly, the volatile regimens through the treatment process makes readers confused, and no evidence supports it. For example, at week 4 posttreatment initiation, the patient had an undetectable viral RNA level and remained negative for the duration of treatment, but the therapy was immediately changed to SOF‐VEL at week 12 for no powerful reason. Moreover, the previously "failed" treatment regime have many common drugs with the current treatment regime, which cannot exclude the possibly subsequent and positive impact of previous treatments on patients. Thirdly, the patient contracted coronavirus disease 19 (COVID‐19) during this course of therapy, which severely influences the antiviral and survival outcome. A multicenter cohort study showed that there is a close association between chronic HCV and COVID‐19.4 The mechanism of liver dysfunction in patients with COVID‐19 includes direct cytopathic effects, immune reaction and cytokine storm‐related multiorgan failure, hypoxia‐reperfusion dysfunction, and drug‐induced liver injury because of the various drugs used for COVID‐19 treatment.5 The treatment outcomes of the patient with HCV may be affected by the influence of COVID‐19 or the cotreatment of COVID‐19. In conclusion, whether extending treatment necessary to successfully induce a durable response among patients with previous treatment failures remains unclear.
Perioperative ctDNA-Based MRD Detection in NSCLC—Response
Authors: Liang Xia, Weizhi Chen, Lunxu Liu
Journal: Clinical Cancer Research (2022)

We thank Wei and colleagues for their interest in our work (1). Their reanalysis of our data indicated a negative correlation of perioperative circulating tumor DNA (ctDNA) levels (based on ctDNA concentration hGE/mL) with recurrence-free survival (RFS) duration across our whole cohort, and suggested further grouping of patients with non–small cell lung cancer (NSCLC) based on their ctDNA levels for recurrence prediction.In fact, we have also assessed the association between RFS and perioperative ctDNA concentration during our initial analysis, with trends agreeing with Wei and colleagues’ analysis. We found that ctDNA concentration was statistically significantly correlated with RFS at postoperative 3 days (P = 0.002) and 1 month (P = 0.001) in all patients, though with relatively weak R values of −0.176 and −0.178, respectively. However, upon performing ROC curve analysis, the optimal cut-off values calculated on ctDNA concentration at these two time points performed equally for recurrence prediction as that of our ctDNA positive/negative calls in terms of sensitivity and specificity. Considering that a universal qualitative classification of ctDNA status is more straightforward and practical in clinical settings, we did not adopt any quantitative cut-off values as suggested by Wei and colleagues because of potential overfitting using the limited number of cohort. In the meantime, at the preoperative time point, we found that the ctDNA concentration's correlation with RFS was not statistically significant (P = 0.362).In summary, we recognize Wei and colleagues’ efforts in exploring the association of ctDNA concentration with RFS and their attempt to identify optimal cut-off values for further stratification. We at the same time notice that this measurement has performed inconsistently across our reported different time points based on our perioperative cohort data, which warrants more investigations in additional longitudinal time points along our LUNGCA trial.See the original Letter to the Editor, p. 3400W. Chen reports a patent for Genecast Biotechnology pending; and in addition, W. Chen is an employee at Genecast Biotechnology. No disclosures were reported by the other authors.
Membrane dual-targeting probes: A promising strategy for fluorescence-guided prostate cancer surgery and lymph node metastases detection
Authors: Ling-Ling Wu, Qinxin Zhao, Qinghua Wang, Qingyang Zhang, Feiya Yang, Bo Zheng, Hai-Yu Hu, Nianzeng Xing
Journal: Acta Pharmaceutica Sinica B (2022)

Fluorescence-guided surgery (FGS) with tumor-targeted imaging agents, particularly those using the near-infrared wavelength, has emerged as a real-time technique to highlight the tumor location and margins during a surgical procedure. For accurate visualization of prostate cancer (PCa) boundary and lymphatic metastasis, we developed a new approach involving an efficient self-quenched near-infrared fluorescence probe, Cy-KUE-OA, with dual PCa-membrane affinity. Cy-KUE-OA specifically targeted the prostate-specific membrane antigen (PSMA), anchored into the phospholipids of the cell membrane of PCa cells and consequently showed a strong Cy7-de-quenching effect. This dual-membrane-targeting probe allowed us to detect PSMA-expressing PCa cells both in vitro and in vivo and enabled clear visualization of the tumor boundary during fluorescence-guided laparoscopic surgery in PCa mouse models. Furthermore, the high PCa preference of Cy-KUE-OA was confirmed on surgically resected patient specimens of healthy tissues, PCa, and lymph node metastases. Taken together, our results serve as a bridge between preclinical and clinical research in FGS of PCa and lay a solid foundation for further clinical research.
Dementia Is More Than Memory Loss: Neuropsychiatric Symptoms of Dementia and Their Nonpharmacological and Pharmacological Management
Authors: Rajesh R. Tampi, Dilip V. Jeste
Journal: American Journal of Psychiatry (2022)

Neuropsychiatric symptoms of dementia (NPS) are a group of noncognitive symptoms that occur in over 90% of individuals with dementia. NPS seem to result from a complex interaction among various biological, psychosocial, and environmental factors, and they are associated with greater morbidity and mortality, higher caregiver burden and burnout, high risk of nursing home placement, and increased cost of care for patients with dementia. Use of standardized assessment tools like the Neuropsychiatric Inventory can assist with qualifying and quantifying NPS. In this review, the authors evaluate the evidence for efficacy and safety of nonpharmacological and pharmacological interventions for treating NPS, mostly based on published meta-analyses. Commonly prescribed medications include atypical antipsychotics, acetylcholinesterase inhibitors, memantine, antidepressants, and mood stabilizers. There are also limited data on cannabinoids, repetitive transcranial magnetic stimulation, and ECT in individuals with NPS. Available evidence indicates that several nonpharmacological interventions are beneficial in the management of NPS and are recommended as first-line treatments. Pharmacotherapy should be reserved for the treatment of more severe or refractory NPS or where nonpharmacological management is not feasible. Atypical antipsychotics have shown mostly modest benefit in reducing NPS, and their use is limited by their adverse effect profiles. Recent investigations suggest potential strategies for preventing or at least reducing the risk of dementia and NPS. The authors conclude with brief guidelines for clinical practice as well as future research.
Customizing nano-chitosan for sustainable drug delivery
Authors: Mostafa Saeedi, Omid Vahidi, Mohammad Reza Moghbeli, Sepideh Ahmadi, Mohsen Asadnia, Omid Akhavan, Farzad Seidi, Mohammad Rabiee, Mohammad Reza Saeb, Thomas J. Webster, Rajender S. Varma, Esmaeel Sharifi, Ali Zarrabi, Navid Rabiee
Journal: Journal of Controlled Release (2022)
A virulence factor as a therapeutic: the probiotic <i>Enterococcus faecium</i> SF68 arginine deiminase inhibits innate immune signaling pathways
Authors: Fereshteh Ghazisaeedi, Jochen Meens, Bianca Hansche, Sven Maurischat, Peter Schwerk, Ralph Goethe, Lothar H. Wieler, Marcus Fulde, Karsten Tedin
Journal: Gut Microbes (2022)

The probiotic bacterial strain Enterococcus faecium SF68 has been shown to alleviate symptoms of intestinal inflammation in human clinical trials and animal feed supplementation studies. To identify factors involved in immunomodulatory effects on host cells, E. faecium SF68 and other commensal and clinical Enterococcus isolates were screened using intestinal epithelial cell lines harboring reporter fusions for NF-κB and JNK(AP-1) activation to determine the responses of host cell innate immune signaling pathways when challenged with bacterial protein and cell components. Cell-free, whole-cell lysates of E. faecium SF68 showed a reversible, inhibitory effect on both NF-κB and JNK(AP-1) signaling pathway activation in intestinal epithelial cells and abrogated the response to bacterial and other Toll-like receptor (TLR) ligands. The inhibitory effect was species-specific, and was not observed for E. avium, E. gallinarum, or E. casseliflavus. Screening of protein fractions of E. faecium SF68 lysates yielded an active fraction containing a prominent protein identified as arginine deiminase (ADI). The E. faecium SF68 arcA gene encoding arginine deiminase was cloned and introduced into E. avium where it conferred the same NF-κB inhibitory effects on intestinal epithelial cells as seen for E. faecium SF68. Our results indicate that the arginine deiminase of E. faecium SF68 is responsible for inhibition of host cell NF-κB and JNK(AP-1) pathway activation, and is likely to be responsible for the anti-inflammatory and immunomodulatory effects observed in prior clinical human and animal trials. The implications for the use of this probiotic strain for preventive and therapeutic purposes are discussed.
Fecal β-glucuronidase activity differs between hematopoietic cell and kidney transplantation and a possible mechanism for disparate dose requirements
Authors: Mohammad Haneef Khan, Guillaume C. Onyeaghala, Armin Rashidi, Shernan G. Holtan, Alexander Khoruts, Ajay Israni, Pamala A. Jacobson, Christopher Staley
Journal: Gut Microbes (2022)

The intestinal microbiota produces β-glucuronidase that plays an essential role in the metabolism of the immunosuppressant mycophenolate mofetil (MMF). This drug is commonly used in organ and hematopoietic cell transplantation (HCT), with variations in dosing across transplant types. We hypothesized that β-glucuronidase activity differs between transplant types, which may account for differences in dosing requirements. We evaluated fecal β-glucuronidase activity in patients receiving MMF post-allogeneic HCT and post-kidney transplant. Kidney transplant patients had significantly greater β-glucuronidase activity (8.48 ± 6.21 nmol/hr/g) than HCT patients (3.50 ± 3.29 nmol/hr/g; P = .001). Microbially mediated β-glucuronidase activity may be a critical determinant in the amount of mycophenolate entering the systemic circulation and an important factor to consider for precision dosing of MMF.